Abstract
Cathepsin K (Cat K) is the primary enzyme involved in Type I collagen degradation in bone resorption. The development of a Cat K inhibitor should provide an effective treatment for osteoporosis. Key components of a clinically viable inhibitor are oral bioavailability, high selectivity over related cathepsins, and a covalent, reversible warhead to bind to the active site cysteine of the enzyme. This article reviews recent advances in the design of inhibitors derived from peptidic leads that contain either a ketone or nitrile electrophile. Three of these compounds have progressed into clinical trials and one, odanacatib (5), is currently in Phase III studies for the treatment of post-menopausal osteoporosis.
Keywords: Osteoporosis, cathepsin K, cysteine protease, lysosomotropism, selective inhibitor, peptidomimetic, bone resorption
Current Topics in Medicinal Chemistry
Title: Peptidomimetic Inhibitors of Cathepsin K
Volume: 10 Issue: 7
Author(s): W. Cameron Black
Affiliation:
Keywords: Osteoporosis, cathepsin K, cysteine protease, lysosomotropism, selective inhibitor, peptidomimetic, bone resorption
Abstract: Cathepsin K (Cat K) is the primary enzyme involved in Type I collagen degradation in bone resorption. The development of a Cat K inhibitor should provide an effective treatment for osteoporosis. Key components of a clinically viable inhibitor are oral bioavailability, high selectivity over related cathepsins, and a covalent, reversible warhead to bind to the active site cysteine of the enzyme. This article reviews recent advances in the design of inhibitors derived from peptidic leads that contain either a ketone or nitrile electrophile. Three of these compounds have progressed into clinical trials and one, odanacatib (5), is currently in Phase III studies for the treatment of post-menopausal osteoporosis.
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Cite this article as:
Cameron Black W., Peptidomimetic Inhibitors of Cathepsin K, Current Topics in Medicinal Chemistry 2010; 10 (7) . https://dx.doi.org/10.2174/156802610791113450
DOI https://dx.doi.org/10.2174/156802610791113450 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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